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OBJECTIVE The goals were to identify predictor variables and to develop scoring systems and classification trees to predict death/disability or death in infants with hypoxic-ischemic encephalopathy. METHODS. Secondary analysis of data from the multicenter, randomized, controlled, National Institute of Child Health and Human Development Neonatal Research Network trial of hypothermia in hypoxioischemic encephalopathy was performed. Data for 205 neonates diagnosed as having hypoxic-ischemic encephalopathy were studied. Logistic regression analysis was performed by using clinical and laboratory variables available within 6 hours of birth, with death or moderate/ severe disability at 18 to 22 months or death as the outcomes. By using the identified variables and odds ratios, scoring systems to predict death/disability or death were developed, weighting each predictor in proportion to its odds ratio. In addition, classification and regression tree analysis was performed, with recursive partitioning and automatic selection of optimal cutoff points for variables. Correct classification rates for the scoring systems, classification and regression tree models, and early neurologic examination were compared. RESULTS. Correct classification rates were 78% for death/disability and 71% for death with the scoring systems, 80% and 77%, respectively, with the classification and regression tree models, and 67% and 73% with severe encephalopathy in early neurologic examination. Correct classification rates were similar in the hypothermia and control groups. CONCLUSIONS. Among neonates diagnosed as having hypoxic-ischemic encephalopathy, the classification and regression tree model, but not the scoring system, was superior to early neurologic examination in predicting death/disability. The 3 models were comparable in predicting death. Only a few components of the early neurologic examination were associated with poor outcomes. These scoring systems and classification trees, if validated, may help in assessments of prognosis and may prove useful for risk-stratification of infants with hypoxic-ischemic encephalopathy for clinical trials. Key Words logistic models, decision trees, asphyxia neonatorum, hypoxia-ischemia, brain, predictive value of tests Abbreviations CART--classification and regression tree GMFCS gross motor function classification system HIE--hypoxic-ischemic encephalopathy ROC--receiver operating characteristic NICHD--National Institute of Child Health and Human Development CI--confidence interval, HYPOXIC-ISCHEMIC ENCEPHALOPATHY (HIE) is a major contributor to neonatal death and morbidity. An estimated 23% of the 4 million neonatal deaths (1) and 8% of all deaths at A recent [...]

A randomized trial of hypothermia in infants is conducted with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Observations suggest that whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

Background. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known. Methods. We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis. Results. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation. Conclusions. Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population. ABBREVIATIONS. PN, parenteral nutrition; ELBW, extremely low birth weight; RIK relative risk; CI, confidence interval., Although glutamine is the most abundant amino acid in both plasma and human milk, (1) it is not included in standard intravenous amino acid solutions because of its limited stability [...]

Context. Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis. Objective. This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results. Methods. VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using [chi square] tests and adjusted comparisons using regression models. Results. Of 9641 VLBW infants who survived >3 days, 2877 (30%) had [greater than or equal to] 1 LPs, and 6056 (63%) had [greater than or equal to] 1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to the (23% vs 2%). Conclusions. Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be under-diagnosed among VLBW infants. Pediatrics 2004;113: 1181-1186; meningitis, sepsis, lumbar puncture, very low birth weight infants., ABBREVIATIONS. LP, lumbar puncture; VLBW, very low birth weight; LOM, late-onset meningitis; NICHD, National Institute of Child Health and Human Development; BC, blood culture; CSF, cerebrospinal fluid; CONS, coagulase-negative staphylococcus; [...]

Objective. Previous multicenter studies have shown significant center differences in neonatal characteristics and morbidities. This study evaluated center differences in outcome at 18 to 22 months among extremely low birth weight (ELBW; 401-1000 g) infants after adjusting for demographics and antenatal interventions, and it identified neonatal interventions associated with outcome differences. Methods. We assessed the outcome of 2478 liveborn infants who were admitted in 1993 and 1994 to the 12 centers of the Neonatal Research Network of the National Institute of Child Health and Human Development; 1483 (60%) infants survived to 18 to 22 months, and 1151 (78%) had comprehensive evaluations. Logistic regression analyses were performed to identify center differences and the association of 4 neonatal interventions--active resuscitation, postnatal steroids, ventilator treatment for [less than or equal to] 27 days, and full enteral feedings [less than or equal to] 24 days--with adverse outcomes (cerebral palsy, low Bayley scores, and neurodevelopmental impairment [NDI]), after adjusting for demographics and antenatal interventions. Results. Using bivariate analyses, significant center differences were identified for mortality, antenatal and postnatal interventions, social and environmental variables, neonatal morbidities, and neurodevelopmental outcomes for the 12 centers. After adjustment for maternal and infant demographics and antenatal interventions, the percentage of ELBW infants who had died or had NDI at 18 to 22 months ranged from 52% to 85%. Active resuscitation and postnatal steroids were associated with increases of NDI of 11.8% and 19.3%, whereas shorter ventilation support and shorter time to achieve full enteral feeds were associated with decreases in NDI of 20.7% and 17.3%, respectively. Conclusion. There are large and disturbing differences among centers in outcomes at 18 to 22 months after adjusting for demographic and antenatal interventions. Center differences in postnatal interventions associated with differences in outcome can provide hypotheses for testing in clinical trials to improve outcome. Pediatrics 2004;113:781-789; extremely low birth weight, center differences, neurologic outcome, developmental outcome, cerebral palsy, Bayley, follow-up studies., Single-center studies of extremely low birth weight (ELBW) infants have reported diverse neonatal and follow-up data, and multicenter studies (1-4) have reported significant differences in neonatal characteristics, morbidities, and care [...]

Objective. To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. Methods. A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) Results. The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI Conclusions. PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI, ABBREVIATIONS. BBCA, bilirubin binding capacity of albumin; ELBW, extremely low birth weight; PSB, peak serum bilirubin; GDB, generic database; CP, cerebral palsy; MDI, Mental Developmental Index; PDI, Psychomotor Developmental Index; [...]

Objective  This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes. Study Design  This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate–severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate–severe impairment defined by any of the following: intelligence quotient <70, moderate–severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy. Results  Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13–0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42–9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment. Conclusion  RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy. Key Points Elevation of specific cytokines and chemokines in neonates with encephalopathy has been noted along with increased risk of neurodevelopmental impairment in infancy. Cytokine/chemokines at <7 days were assessed among neonates in a trial of hypothermia for HIE. Neonates who died or were impaired at 6 to 7 years following hypoxic-ischemic encephalopathy had lower RANTES and higher MCP-1 levels than those who survived without impairment. [ABSTRACT FROM AUTHOR]

Objective. Modest reduction in brain temperature is a promising therapy to reduce brain damage after neonatal encephalopathy as a result of acute perinatal asphyxia. The efficacy of modest hypothermia may in part be dependent on the stability of the desired brain temperature. The objective of this study was 1) to evaluate in newborn animals a commercially available cooling system (Blanketrol II Hyperthermia-Hypothermia system) to control brain temperature during whole-body hypothermia and 2) to use the results of the animal experiments to perform a pilot study evaluating the feasibility of whole-body hypothermia as a neuroprotective therapy for newborns with encephalopathy at birth. Methods. In the animal investigation, 3 miniature swine were instrumented and ventilated, and temperature probes were placed in the esophagus and the brain (1 cm and 2 cm beneath the parietal cortical surface and the dura). Body cooling was achieved using the automatic control mode (servo) of the cooling system. In the human investigation, 19 term infants with moderate or severe encephalopathy were randomized to either normothermia (n = 10) or hypothermia (n = 9) within 6 hours of birth. Whole-body hypothermia was achieved using the hyperthermia-hypothermia cooling system with servo control of esophageal temperature to 34.5[degrees]C for 72 hours followed by slow rewarming. Results. In the animal investigation, body cooling with the animal lying on a single blanket resulted in rapid cooling of the body within 90 minutes. Repetitive cyclical swings in esophageal temperature of 1.7 [+ or -] 0.2[degrees]C (mean [+ or -] standard deviation) around the set point of 33.5[degrees]C were reduced to 0.7 [+ or -] 0.2[degrees]C when a second, larger blanket was attached and suspended. Esophageal temperature was a good marker of deep brain temperature (esophageal to 2-cm brain difference: 0.1 [+ or -] 0.3[degrees]C). In the human investigation, the infants were randomized at 4.1 [+ or -] 1.3 hours (mean [+ or -] standard deviation) after birth. Age at randomization was similar in the 2 groups. Cooling was initiated at an average age of 5.3 hours. Target temperature of 34.5[degrees]C was achieved within 30 minutes and remained constant throughout the intervention period. Heart rate decreased to 108 [+ or -] 14 beats per minute (bpm) at 60 minutes and remained between 115 and 130 bpm for the duration of cooling compared with 130 to 145 bpm in the normothermia group. Blood pressure was similar in the 2 groups. No adverse events occurred during 72 hours of cooling. The mortality rate and frequency of persistent pulmonary hypertension, renal failure, hepatic dysfunction, and need for pressor support were similar in both groups. Conclusions. Animal studies showed that a simple modification of a commercially available cooling system (2 blankets attached, subject lying on 1 and the second hanging freely) results in stable core body and brain temperature when used in the automatic control mode. The pilot study in term infants with encephalopathy using this cooling system demonstrates feasibility of initiating whole-body hypothermia at, ABBREVIATIONS. HIE, hypoxic-ischemic encephalopathy; bpm, beats per minute; MRI, magnetic resonance imaging; SD, standard deviation; aEEG, amplitude-integrated EEG. Hypoxic-ischemic encephalopathy (HIE) associated with acute perinatal asphyxia in the term or [...]

Objective. Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 6956 VLBW (401-1500 g) neonates admitted to the clinical centers of the National Institute of Child Health and Human Development Neonatal Research Network over a 2-year period (1998-2000). Methods. The National Institute of Child Health and Human Development Neonatal Research Network maintains a prospective registry of all VLBW neonates admitted to participating centers within 14 days of birth. Expanded infection surveillance was added in 1998. Results. Of 6215 infants who survived beyond 3 days, 1313 (21%) had 1 or more episodes of blood culture-proven late-onset sepsis. The vast majority of infections (70%) were caused by Gram-positive organisms, with coagulase-negative staphylococci accounting for 48% of infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of late-onset sepsis included patent ductus arteriosus, prolonged ventilation, prolonged intravascular access, bronchopulmonary dysplasia, and necrotizing enterocolitis. Infants who developed late-onset sepsis had a significantly prolonged hospital stay (mean length of stay: 79 vs 60 days). They were significantly more likely to die than those who were uninfected (18% vs 7%), especially if they were infected with Gram-negative organisms (36%) or fungi (32%). Conclusions. Late-onset sepsis remains an important risk factor for death among VLBW preterm infants and for prolonged hospital stay among VLBW survivors. Strategies to reduce late-onset sepsis and its medical, social, and economic toll need to be addressed urgently. Pediatrics 2002;110:285-291; sepsis, infant, newborn infant, very low birth weight infant, premature., ABBREVIATIONS. VLBW, very low birth weight; NICHD, National Institute of Child Health and Human Development; CRP, C-reactive protein; CONS, coagulase-negative staphylococci; GA, gestational age; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; [...]

Very-low-birth-weight babies who develop a bacterial blood infection are more likely to be infected with E. coli than with group B streptococci. These babies are three times more likely to die than babies who are not infected. In a study of 5,447 babies, 85% of the E. coli strains were resistant to the antibiotic ampicillin.

Objective. To quantify differences in resource expenditure in the perinatal period and long-term outcome of extremely premature infants who received systematically different approaches to neonatal intensive care. Methods. Perinatal management, mortality, prevalence of disabling cerebral palsy (DCP), and resource expenditure of 2 population-based inception cohorts of extremely premature infants born in the mid-1980s were compared. Electronic fetal monitoring, tocolysis, cesarean section delivery, and assisted ventilation were used to characterize management approaches. Participants included all live births at 23 to 26 weeks&apos; gestation in a 3-county area of central New Jersey (NJ) from 1984 to 1987 (N = 146) and throughout the Netherlands (NETH) in 1983 (N = 142). Mortality and the prevalence of DCP were the primary outcomes. Numbers of hospital days with and without assisted ventilation were the measures of resource expenditure. Results. Electronic fetal monitoring (100% vs 38%), cesarean section (28% vs 6%), and assisted ventilation (95% vs 64%) were all more commonly used in NJ than in NETH. Ten percent of NJ deaths occurred without assisted ventilation, compared with 45% of Dutch deaths. A total of 1820 ventilator days were expended per 100 live births in NJ, compared with 448 in NETH. The increase in the number of nonventilator days (3174 vs 2265 days per 100 live births) did not reach statistical significance. Survival to age 2 (46 vs 22%) and the prevalence of DCP among survivors (17.2 vs 3.4%) were significantly greater in NJ at age 2 than in NETH at age 5. Conclusions. Near universal initiation of intensive care in NJ, compared with selective initiation of intensive care in NETH, was associated with 24.1 additional survivors per 100 live births, 7.2 additional cases of DCP per 100 live births, and a cost of 1372 additional ventilator days per 100 live births. Pediatrics 2001;108:1269-1274; extreme prematurity, mortality, cerebral palsy, neonatal intensive care., ABBREVIATIONS. NETH, the Netherlands; NBH, neonatal brain hemorrhage; NJ, New Jersey; POPS, Project on Preterm and Small for Gestational Age Infants; EFM, electronic fetal monitoring; DCP, disabling cerebral palsy; CP, [...]

Low-dose dexamethasone does not prevent lung disease in extremely premature babies and has significant side effects, according to a study of 220 babies with birth weights between 500 and 1,000 grams. About 30% of all extremely-low-birth-weight babies develop chronic lung disease.

Intramuscular injections of vitamin A three times a week for several weeks appears to improve lung function in extremely-low-birth-weight babies. These infants have a high risk of lung diseases caused by extreme prematurity. Researchers randomly assigned 807 such infants to receive intramuscular shots of vitamin A or a placebo. Only 55% of the infants who received vitamin A died or developed lung disease compared to 62% of those who received placebo.

It does not appear to be beneficial to give dexamethasone to infants on ventilators any earlier than 4 weeks of age. Dexamethasone is believed to improve lung function and make it easier to take the infant off the ventilator. Researchers compared outcomes in 371 premature infants on a ventilator who were given dexamethasone at 2 weeks of age or at 4 weeks. The earlier administration of the drug did not significantly improve outcomes and increased the risk of hospital-acquired bacterial infections and hyperglycemia.

There are many factors that may determine whether a premature infant should receive mechanical ventilation. In a study of 1,126 infants weighing between 501 and 800 grams at birth, overall mortality was 43%. Mortality in those who did not receive mechanical ventilation was 93%. Female babies, those who were small for gestational age and those whose mothers received corticosteroids were more likely to benefit from mechanical ventilation. These infants used a significant amount of resources, but the cost per life-year gained was probably small.

Small-for-gestational-age (SGA) infants appear to be at equal or greater risk for respiratory distress syndrome (RDS) compared with appropriate-for-gestational-age (AGA) infants. SGA infants are conventionally considered to have accelerated lung maturity and thus to be at lower risk for RDS. Records were evaluated for all singleton infants born between 25 and 42 weeks gestation at Parkland Memorial, a Dallas hospital, between 1977 and 1980. Parkland serves mostly indigent black and Hispanic patients. Several different means of determining SGA and AGA status were used. Regardless of how SGA was determined, SGA infants fared no better with respect to RDS, and in some analyses, they fared worse. This evidence suggests that the SGA fetus should not be assumed to be at lower risk for RDS upon birth., ABSTRACT. Objective. Small for gestational age (SGA) neonates have been considered to have accelerated pulmonary maturation and thus a lower risk for respiratory distress syndrome (RDS) than appropriate for gestational [...]

The prophylactic use of intravenous immune globulin does not appear to reduce the rate of hospital-acquired infections in very-low-birthweight infants. Hospital-acquired infections are responsible for many deaths of very-low-birthweight babies due to their long hospital stays and reduced levels of IgG, a type of immunoglobulin that protects against certain infections. A group of 1204 very-low-birthweight infants (